Prostate cancer is one of the frequently detected cancers in males and the second leading cause of death in males. Vitamin D analogues are widely used for prostate cancer chemotherapy and exerts its anti-proliferative activities through the Vitamin D receptor (VDR) signaling pathway. The p63 gene, a member of the p53 tumor suppressor gene family, plays a critical role in prostate development. Mice lacking p63 exhibit not only severe developmental defects but lack a prostate organ as well. Recently, epithelial stem cells have been implicated in prostate growth and disease. p63 is expressed in the basal cells of the prostate and abnormal p63 expression has been associated with neoplastic transformation of the prostate. The complex structure of p63 gives rise to six different isoforms that either act as transcriptional activators or repressors. The balance between the levels of different p63 isoforms plays an important role in deciding the fate of cell proliferation/differentiation. Preliminary data in our laboratory demonstrated that TAp63 expression leads to the induction of several genes involved in the VDR pathway. This research proposal is aimed at dissecting the role of p63 in the VDR signaling pathway and subsequently its role in prostate cancer progression. Our hypothesis is that p63 isoforms exert differential effects on cell growth and survival through regulation of the VDR pathway. The research effort proposed here may not only reveal important information about the role of p63 and VDR signaling in understanding the development of prostate cancer but assist in the development of therapeutic strategies in the treatment of prostate cancer. [unreadable] [unreadable] [unreadable]